Working memory training for pediatric cancer survivors

Summary
Cure rates for childhood cancer survivors have increased markedly over the last fifty years to nearly 80%. Despite the favorable prognosis for survival, patients are at high risk for both acute and late-occurring sequelae associated with their disease and treatments. For example, reports from the Childhood Cancer Survivors Study have consistently documented survivors’ increased risk for secondary malignancies, cardiovascular disease, obesity, and diminished quality of life. As a result, increased empirical attention has been focused in recent years on the long-term consequences of survival.

While all long-term pediatric patients are at high-risk for both late-occurring physiologic and psychosocial effects of cancer therapy, children who receive therapies that impact the central nervous system (ie., intrathecal methotrexate, cranial radiation, neurosurgery) are at even higher risk for cognitive, social, and psychological disorders. This is especially true for survivors of acute lymphoblastic leukemia (ALL) and primary brain tumors, which together account for over half of all new childhood cancer diagnoses. Indeed, various studies have shown that 40 to 100 percent of survivors of pediatric brain tumors will evidence some sort of cognitive deficit resulting from a combination of disease and treatment variables. In addition, at least 30 percent of survivors of ALL will experience some degree of neurocognitive deficit. The impact of both the disease and its treatments can have deleterious effects on the brain and cognitive functioning of these survivors, with younger age at diagnosis, longer time since diagnosis, and female sex increasing the risk of neurocognitive late effects.

Deficits in attention and working memory
Findings from the last decade suggest that declines in intelligence (ie., IQ) and achievement observed in childhood cancer survivors are secondary to cognitive processing deficits involving attention, short-term memory, speed of processing, visuomotor coordination and/or sequencing abilities. Most relevant to the goals of the current proposal is evidence of specific attentional deficits among survivors. In general, problems involve reaction time, shifting of attention, and sustained attention. Moreover, broad deficits with working memory (WM), particularly for visual stimuli, have been documented. Deficits appear worse in survivors who have been treated with cranio-spinal irradiation (CSI). For example, Reeves and colleagues recently examined attention and memory functioning prior to, and two years after, receiving CSI in 38 children.

Following CSI, the investigators found that survivors’ visual attention was markedly impaired compared to the standardization sample. Specifically, survivors evidenced difficulties with selective attention, made slow or inconsistent responses, and showed poor sustained attention over the course of a 14-minute computerized task of visual attention. In contrast, though survivors’ verbal memory skills declined compared to baseline levels, they were not significantly different from scores of the standardization sample at follow-up. With regard to WM, Reimers and colleagues assessed functioning in 126 survivors of pediatric brain tumors. The authors found that both visual and verbal WM were moderately impaired. Again, children treated with CSI performed more poorly on WM tasks than children without this treatment history.

Although attention and memory deficits appear to be more robust in survivors of pediatric brain tumors, similar difficulties have been documented in survivors of ALL. Buizer and colleagues for example, compared attention functioning and information processing in 36 survivors of ALL treated with methotrexate (MTX) to 39 survivors of Wilms’ tumor and 110 healthy children. Survivors of ALL treated with standard MTX evidenced significant difficulties with attentional flexibility, but were otherwise comparable to healthy children. In addition, ALL patients treated with high-dose MTX also had decreased sustained attention and visual-motor control compared to the control groups. As with survivors of pediatric brain tumors, children with ALL who received radiation therapy evidence greater attention and memory problems. In a study of 27 long-term survivors of ALL treated with radiation, significant deficits in working memory for both verbal and spatial information were observed.

Notably, difficulties with attention are significantly correlated with problems in higher-order cognitive processes such as memory and learning tasks. Indeed, many investigators have posited that attention and WM deficits underlie changes in IQ and academic performance frequently seen in survivors of both ALL and brain tumors. In healthy children, Fry and Hale found that almost half of developmental increases in IQ could be attributed to age-related improvements in WM and processing speed.

Similar findings have been documented in pediatric cancer survivors; Schatz and colleagues, for example, found that 45 percent of the variance in IQ was attributable to these processes. In addition, 70 percent of survivors’ functional impairments were accounted for by attention problems in a study conducted by Reddick and colleagues.

The developmental importance of attentional processes has been underscored by recent neuro-imaging studies with childhood cancer survivors. Specifically, recent investigations have suggested that many of the neurocognitive deficits experienced by survivors are associated, in large part, with changes in normal-appearing white matter (NAWM). NAWM is known to be damaged by treatment with CSI and some chemotherapy agents. Reddick and colleagues tested a model relating NAWM to neurocognitive function in 40 survivors of pediatric brain tumors who had received chemotherapy and/or radiation. Findings revealed that declining IQ and academic achievement scores were a direct result of attentional deficits, which, in turn, were caused by reduction in NAWM. As such, the study identified attentional processes as critical targets of intervention “to avoid or minimize the impact of therapy on the quality of life for pediatric BT survivors” (p.2518). Therefore, focus must be turned towards designing and implementing interventions that target the neurocognitive properties that influence cognition, particularly attention skills.

Existing intervention efforts: Based on evidence of robust attention and working memory deficits in many survivors of CNS-impacting cancer in children, researchers have begun to investigate the efficacy of empirically-supported treatments for these impairments. These efforts have historically focused on compensation for acquired deficits rather than restoration of functioning. Indeed, current standard-of-care for survivors with cognitive and academic late-effects emphasizes school-based accommodations such as preferential seating and extended time for in-class assignments and examinations. Research to examine the efficacy of educational supports for survivors of pediatric cancer is underway, though the wide variability in access to, and quality of, school-based accommodations likely will make it difficult to generalize findings to a broad group of survivors. Clearer evidence exists to support specific educational tutoring programs, which show some efficacy at improving selected academic skills (ie., math) for some children. Of importance, however, such accommodations do not specifically address the cognitive deficits that underlie survivors’ academic problems.

In order to target broader neurocognitive processes, recent intervention efforts including pharmacotherapy and cognitive remediation have been tested with survivors. Specifically, the psychostimulant methylphenidate (MPH) has contributed to improved functioning in both adult brain tumor patients and survivors of childhood cancer. In the largest trial to date, Mulhern and colleagues found both statistically significant and clinically meaningful results for the use of MPH with survivors of ALL and brain tumors, including a reduction in attentional and social deficits over the course of a three-week trial. Despite the initial positive findings for the use of psychostimulants such as MPH with childhood cancer survivors, there are some concerns including adverse effects in a small group of participants, unknown long-term efficacy, and reluctance on the part of some parents to administer more medication to their already “medically fragile” survivors.

Preliminary studies also have been conducted with cognitive remediation for survivors of CNS-impacting cancer in childhood. These programs focus on the acquisition of strategies designed to improve performance on cognitive and academic outcomes and also on attentional skills and consist of a two-hour session with a therapist every week for six months. While this program has shown preliminary efficacy with small groups of CNS-impacting childhood cancer survivors, effect sizes for many indices of academic and adaptive functioning are small. Moreover, the mode of treatment makes it impractical for larger groups of survivors who may live far away from a medical center that could provide the program. Indeed, 40 percent of participants in this program failed to complete the treatment. Therefore it is critical that effective short-term and home-based interventions be developed so as to be applicable to a wide-range of potential participants, who will not be limited by time, distance or cost.

Aim
The intent of the current study is to assess the feasibility and acceptability of a home-based, computerized attention training program with survivors of central nervous system impacting pediatric cancer (ie., acute lymphoblastic leukemia, brain tumors). It is hypothesized that home-based computerized attention training program will be feasible and acceptable for survivors of pediatric cancer as measured by parent and child report of technical ease-of-use and satisfaction and program records of treatment compliance.

Another aim of this project is to estimate the effect size of this attention training program with survivors of childhood cancer to determine whether a larger-scale clinical trial is warranted.

Researchers posit that participants who successfully complete the intervention will show increases in attention and working memory of moderate effect size at the end of the intervention period as compared to baseline functioning and to participants who complete a placebo condition of the program. Further, participants who successfully complete the intervention will maintain increased attention and working memory scores (compared to baseline) after a three-month follow-up period.